Ribosomal tunnel

The ribosomal tunnel, or peptide tunnel, is a part of the ribosome that holds the nascent polypeptide chain during translation.[1] The ribosomal tunnel is located in the large subunit of the ribosome and connects the catalytic site of the ribosome with its surface.[2]

History

The existence of the ribosomal tunnel became apparent in the 1960s.[3] When the nascent protein was exposed to hydrolytic enzymes, part of the protein was protected from hydrolysis, supporting the hypothesis of the existence of a tunnel that shields part of the protein.[4] The tunnel was then identified in the large subunit of the ribosome by cryogenic electron microscopy.[5] Crucial information about the existence of the tunnel was provided by atomically resolved structures of the large ribosomal subunit determined by X-ray crystallography by the research group of Thomas Steitz.[6] In 2009, Thomas Steitz, along with A. Yonath and V. Ramakrishnan, received the Nobel Prize in Chemistry for their research on the ribosome.

The initial view that the tunnel is merely an inert environment through which the nascent polypeptide exits the ribosome has been abandoned based on numerous studies. Today, it is believed that the tunnel is actively involved in regulating translation and maintaining homeostasis.[2]

Tunnel structure

The shape of the ribosomal tunnel is irregular, and its size varies depending on the organism and cell type.[7] Ribosomal tunnels in bacteria are generally longer and wider than those in the ribosomes of higher organisms. In bacteria, the tunnel length is approximately 9.2 nm, while in eukaryotes it is about 8.3 nm and the average radius of the ribosomal tunnel is on average 0.57 nm in bacteria and 0.51 nm in eukaryotes. The tunnel can accommodate a polypeptide consisting of around 40 to 60 amino acid residues.[8]

The tunnel walls are composed of rRNA and several ribosomal proteins.[9] The tunnel is filled with water and ions, while small molecules such as ornithine may diffuse into it. The tunnel contains a constriction formed by loops of ribosomal proteins uL4 and uL22, which divide the tunnel space into an inner and an outer part (sometimes also referred to as the upper and lower parts). The inner portion near the catalytic site is approximately 3.5 nm long and accommodates a nascent polypeptide of 12 to 16 amino acid residues. There is a second constriction in the ribosomes of some eukaryotes[10] that has implications for the regulation of short peptide synthesis.[11]

The outer part of the tunnel widens toward its opening and forms the so-called vestibule. The opening of the tunnel is flanked by the ribosomal proteins uL23, uL24, uL29 and uL32. In eukaryotes, also uL35, uL39e, or uL25.[2] Ribosome-associated protein biogenesis factors such as the trigger factor or peptide deformylase bind to their vicinity.

Effect on Proteosynthesis

As the nascent polypeptide elongates during proteosynthesis, it passes through the ribosomal tunnel, interacting with the tunnel walls, thus regulating the rate at which it passes through the tunnel.[1][12] This in turn affect the rate of partial folding, which may already occur at this stage. Short stretches of alpha-helix may form in the inner part of the tunnel and tertiary structure may start forming in the wider tunnel vestibule.[13][14] As the N-terminus reaches the tunnel exit and is processed by the ribosome-associated protein biogenesis factors, the tertiary structure formed in the tunnel may partially refold.[15] The folding is then completed when the C-terminus is released from the PTC and the protein escapes the tunnel.[1][2]

Interaction with Antibiotics

The ribosomal tunnel contains binding sites for clinically important antibiotics, such as macrolides or streptogramins.[16][17][18] Antibiotics bind to the inner part of the ribosomal tunnel, either near the peptidyl transferase center or near the constriction site.[9][17] Despite the original belief that macrolide binding to the tunnel causes obstruction, it has been shown that the tunnel remains permeable. Antibiotics instead stabilize the catalytic site of the ribosome in a conformation that is unproductive for peptide bond formation, causing translational arrest.[17] Translational arrest of the ribosome may also be dependent on the sequence of the nascent peptide, as has been observed, for example with chloramphenicol.[19]

See also

References

  1. ^ a b c Kolář, Michal H.; McGrath, Hugo; Nepomuceno, Felipe C.; Černeková, Michaela (4 November 2024). "Three Stages of Nascent Protein Translocation Through the Ribosome Exit Tunnel". WIREs RNA. 15 (6) e1873. arXiv:2404.09728. doi:10.1002/wrna.1873. ISSN 1757-7004. PMID 39496527. Retrieved 24 February 2025.
  2. ^ a b c d Wilson, Daniel N; Beckmann, Roland (April 2011). "The ribosomal tunnel as a functional environment for nascent polypeptide folding and translational stalling". Current Opinion in Structural Biology. 21 (2): 274–282. doi:10.1016/j.sbi.2011.01.007. PMID 21316217.
  3. ^ Malkin, Leonard I.; Rich, Alexander (14 June 1967). "Partial resistance of nascent polypeptide chains to proteolytic digestion due to ribosomal shielding". Journal of Molecular Biology. 2 (26): 329–346. doi:10.1016/0022-2836(67)90301-4. PMID 4962271. Retrieved 24 February 2025 – via Elsevier Science Direct.
  4. ^ LeBouton, A. V.; Masse, J. Peters (October 1981). "Ultrastructural immunocytochemistry of nascent albumin topology: Proposed cytosolic folding and membrane transit of the protein". The Anatomical Record. 2 (201): 203–223. doi:10.1002/ar.1092010202. ISSN 0003-276X. PMID 7032362. Retrieved 24 February 2025.
  5. ^ Frank, Joachim; Zhu, Jun; Penczek, Pawel; Li, Yanhong; Srivastava, Suman; Verschoor, Adriana; Radermacher, Michael; Grassucci, Robert; Lata, Ramani K.; Agrawal, Rajendra K. (August 1995). "A model of protein synthesis based on cryo-electron microscopy of the E. coli ribosome". Nature. 376 (6539): 441–444. Bibcode:1995Natur.376..441F. doi:10.1038/376441a0. ISSN 0028-0836. PMID 7630422.
  6. ^ Ban, Nenad; Nissen, Poul; Hansen, Jeffrey; Moore, Peter B.; Steitz, Thomas A. (2000-08-11). "The Complete Atomic Structure of the Large Ribosomal Subunit at 2.4 Å Resolution". Science. 289 (5481): 905–920. Bibcode:2000Sci...289..905B. doi:10.1126/science.289.5481.905. ISSN 0036-8075. PMID 10937989.
  7. ^ Bogdanov, A. A.; Sumbatyan, N. V.; Shishkina, A. V.; Karpenko, V. V.; Korshunova, G. A. (December 2010). "Ribosomal tunnel and translation regulation". Biochemistry (Moscow). 75 (13): 1501–1516. doi:10.1134/S0006297910130018. ISSN 0006-2979. PMID 21417991 – via Springer.
  8. ^ Dao Duc, Khanh; Batra, Sanjit S; Bhattacharya, Nicholas; Cate, Jamie H D; Song, Yun S (2019-05-07). "Differences in the path to exit the ribosome across the three domains of life". Nucleic Acids Research. 47 (8): 4198–4210. doi:10.1093/nar/gkz106. ISSN 0305-1048. PMC 6486554. PMID 30805621.
  9. ^ a b Worthan, Sarah B.; Franklin, Elizabeth A.; Pham, Chi; Yap, Mee-Ngan F.; Cruz-Vera, Luis R. (2022-04-27). Oglesby, Amanda G. (ed.). "The Identity of the Constriction Region of the Ribosomal Exit Tunnel Is Important to Maintain Gene Expression in Escherichia coli". Microbiology Spectrum. 10 (2). Peter Lund: e0226121. doi:10.1128/spectrum.02261-21. ISSN 2165-0497. PMC 9045200. PMID 35311583.
  10. ^ Dao Duc, Khanh; Batra, Sanjit S; Bhattacharya, Nicholas; Cate, Jamie H D; Song, Yun S (2019-05-07). "Differences in the path to exit the ribosome across the three domains of life". Nucleic Acids Research. 47 (8): 4198–4210. doi:10.1093/nar/gkz106. ISSN 0305-1048. PMC 6486554. PMID 30805621.
  11. ^ Yu, Shiqi; Srebnik, Simcha; Dao Duc, Khanh (January 2023). "Geometric differences in the ribosome exit tunnel impact the escape of small nascent proteins". Biophysical Journal. 122 (1): 20–29. Bibcode:2023BpJ...122...20Y. doi:10.1016/j.bpj.2022.11.2945. PMC 9822834. PMID 36463403.
  12. ^ Wilson, Daniel N; Arenz, Stefan; Beckmann, Roland (April 2016). "Translation regulation via nascent polypeptide-mediated ribosome stalling". Current Opinion in Structural Biology. 37: 123–133. doi:10.1016/j.sbi.2016.01.008. PMID 26859868.
  13. ^ Bhushan, Shashi; Gartmann, Marco; Halic, Mario; Armache, Jean-Paul; Jarasch, Alexander; Mielke, Thorsten; Berninghausen, Otto; Wilson, Daniel N; Beckmann, Roland (March 2010). "α-Helical nascent polypeptide chains visualized within distinct regions of the ribosomal exit tunnel". Nature Structural & Molecular Biology. 17 (3): 313–317. doi:10.1038/nsmb.1756. hdl:11858/00-001M-0000-0010-7BCB-0. ISSN 1545-9993. PMID 20139981.
  14. ^ Nilsson, Ola B.; Hedman, Rickard; Marino, Jacopo; Wickles, Stephan; Bischoff, Lukas; Johansson, Magnus; Müller-Lucks, Annika; Trovato, Fabio; Puglisi, Joseph D.; O'Brien, Edward P.; Beckmann, Roland; von Heijne, Gunnar (September 2015). "Cotranslational Protein Folding inside the Ribosome Exit Tunnel". Cell Reports. 12 (10): 1533–1540. doi:10.1016/j.celrep.2015.07.065. PMC 4571824. PMID 26321634.
  15. ^ Holtkamp, Wolf; Kokic, Goran; Jäger, Marcus; Mittelstaet, Joerg; Komar, Anton A.; Rodnina, Marina V. (2015-11-27). "Cotranslational protein folding on the ribosome monitored in real time". Science. 350 (6264): 1104–1107. Bibcode:2015Sci...350.1104H. doi:10.1126/science.aad0344. ISSN 0036-8075. PMID 26612953.
  16. ^ Bock, Lars V; Kolář, Michal H; Grubmüller, Helmut (April 2018). "Molecular simulations of the ribosome and associated translation factors". Current Opinion in Structural Biology. 49: 27–35. arXiv:1711.06067. doi:10.1016/j.sbi.2017.11.003. PMID 29202442.
  17. ^ a b c Wilson, Daniel N. (January 2014). "Ribosome-targeting antibiotics and mechanisms of bacterial resistance". Nature Reviews Microbiology. 12 (1): 35–48. doi:10.1038/nrmicro3155. ISSN 1740-1526. PMID 24336183.
  18. ^ Jenni, S (April 2003). "The chemistry of protein synthesis and voyage through the ribosomal tunnel". Current Opinion in Structural Biology. 13 (2): 212–219. doi:10.1016/S0959-440X(03)00034-4. PMID 12727515.
  19. ^ Xue, Liang; Spahn, Christian M. T.; Schacherl, Magdalena; Mahamid, Julia (February 2025). "Structural insights into context-dependent inhibitory mechanisms of chloramphenicol in cells". Nature Structural & Molecular Biology. 32 (2): 257–267. doi:10.1038/s41594-024-01441-0. ISSN 1545-9993. PMC 11832420. PMID 39668257.
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